Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.

The proproliferative transcription factor KLF5 plays an important role in promoting cell proliferation and tumorigenesis. KLF5 is a short-lived protein that can be rapidly degraded through the ubiquitin-proteasome pathway in cancer cells. However, the mechanisms regulating protein stability remain poorly understood. In this study, the tumor suppressor Fbw7, a component of the SCF complex (SCF Fbw7 ) E3 ubiquitin ligase, specifically promoted the degradation and ubiquitination of KLF5 but had little effect on the stability of KLF4. Fbw7 interacted with KLF5 in a CDC4 phosphodegron (CPD)-dependent manner. Three CPDs were found in the KLF5 protein. Simultaneous mutation of these CPDs significantly abolished Fbw7-mediated ubiquitination and degradation. Furthermore, Fbw7 deficiency dramatically delayed KLF5 turnover and led to the accumulation of KLF5 protein in cancer cells. Glycogen synthase kinase-3␤ could phosphorylate and promote Fbw7-mediated KLF5 degradation. More importantly, Fbw7 negatively regulated the biological activity of KLF5 in gene regulation and cell proliferation. Taken together, these data indicate that Fbw7 is a key negative regulator controlling KLF5-mediated cell proliferation and suggest an additional mechanism linking the loss of Fbw7 function to tumorigenesis. Sp/Krüppel-like factor (KLF) 2 transcription factors are involved in various biological processes and human diseases (1, 2). KLF5 (also known as IKLF and BTEB2) is a basic KLF transcription factor that regulates cell proliferation and plays an important role in diverse physiological and pathological processes, including stemness, inflammation, and atherogenesis (3, 4). As a proproliferative factor, KLF5 also has essential functions in tumorigenesis (3). Increasing evidence indicates that KLF5 can function as an oncogenic protein by promoting cell proliferation in many cancers (5-10). For example, a high expression level of KLF5 correlates with a shorter survival time in breast cancer patients (11). Inhibition of KLF5 expression by pharmacological or genetic methods significantly reduces colorectal cancer cell proliferation (6, 12). However, under certain conditions, KLF5 can also act as a tumor suppressor in some cancers (13,14). The exact mechanisms underlying these apparently contradictory functions are not completely understood.The function of KLF5 is regulated at multiple levels. KLF5 transcription is regulated by several signaling molecules such as Wnt and lysophosphatidic acid (15,16). At the post-translational level, KLF5 function is modulated by phosphorylation, sumoylation, and acetylation (3). Phosphorylation of KLF5 by protein kinase C enhances its transactivation activity and its interaction with CBP (cAMP-responsive element-binding protein-binding protein) (17), whereas sumoylation regulates KLF5-mediated lipid metabolism and its subcellular localization (18,19).KLF5 is an unstable protein with a short half-life in cells. Its protein levels are regulated negatively by the ubiquitin-proteasome pathway (20). The E3 ubiquiti...

Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure–activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.

No abstract

Orientation and alignment of molecules by ultrashort laser pulses is crucial for a variety of applications and has long been of interest in physics and chemistry, with the special emphasis on stereodynamics in chemical reactions and molecular orbitals imaging. As compared to the laser-induced molecular alignment, which has been extensively studied and demonstrated, achieving molecular orientation is a much more challenging task, especially in the case of asymmetric-top molecules. Here, we report the experimental demonstration of all-optical field-free three-dimensional orientation of asymmetric-top molecules by means of phase-locked cross-polarized two-color laser pulse. This approach is based on nonlinear optical mixing process caused by the off-diagonal elements of the molecular hyperpolarizability tensor. It is demonstrated on SO2 molecules and is applicable to a variety of complex nonlinear molecules.

We experimentally visualize the dissociative frustrated double ionization of hydrogen molecules by using few-cycle laser pulses in a pump-probe scheme, in which process the tunneling ionized electron is recaptured by one of the outgoing nuclei of the breaking molecule. Three internuclear distances are recognized to enhance the dissociative frustrated double ionization of molecules at different instants after the first ionization step. The recapture of the electron can be further steered to one of the outgoing nuclei as desired by using phase-controlled two-color laser pulses. Both the experimental measurements and numerical simulations suggest that the Rydberg atom is favored to emit to the direction of the maximum of the asymmetric optical field. Our results on the one hand intuitively visualize the dissociative frustrated double ionization of molecules, and on the other hand open the possibility to selectively excite the heavy fragment ejected from a molecule.

We give a notion of branching systems on ultragraphs. From this we build concrete representations of ultragraph C*-algebras on the bounded linear operators of Hilbert spaces. To each branching system of an ultragraph we describe the associated Perron-Frobenius operator in terms of the induced representation. We show that every permutative representation of an ultragraph C*-algebra is unitary equivalent to a representation arising from a branching system. We give a sufficient condition on ultragraphs such that a large class of representations of the C*-algebras of these ultragraphs is permutative. To give a sufficient condition on branching systems so that their induced representations are faithful we generalize Szymański's version of the Cuntz-Krieger uniqueness theorem for ultragraph C*-algebras.Ultragraphs are combinatorial objects that generalize directed graphs. Roughly speaking an ultragraph is a graph where the image of the range map does not belong to the set of vertices, but instead to the power set on vertices. The concept was introduced by Mark Tomforde in [24] with an eye towards C*-algebra applications. In particular, Tomforde showed in [24] how to associate a C*-algebra to an ultragraph and proved that there exist ultragraph C*-algebras that are neither Exel-Laca algebras nor graph C*-algebras. So the study of ultragraph C*-algebras is of interest, but furthermore, ultragraph C*-algebras were key in answering the long-standing question of whether an Exel-Laca algebra is Morita equivalent to a graph algebra (see [16]).Recently the scope of ultragraphs has surpassed the realm of C*-algebras, reaching applications to symbolic dynamics. In particular, ultragraphs are fundamental in characterizing one-sided shift spaces over infinite alphabets. Furthermore, questions regarding the dynamics of one-sided shift spaces over infinite alphabets were answered using ultragraphs and their C*-algebras (see [13]).The above evidence leads us to believe that there are still many applications of ultragraphs to be found. Indeed, among the results we present in this paper, we will show a connection (via branching systems) between ultragraphs and the Perron-Frobenius operator from the ergodic theory (see Section 5), therefore generalizing results previously obtained for graph algebras and Cuntz-Krieger C*-algebras (see [10,12]).Branching systems are not just important as a way to connect ultragraphs to the ergodic theory. They have appeared in fields as random walks, symbolic dynamics, wavelet theory and are strongly connected to the representation theory of combinatorial algebras. In particular, Bratteli and Jorgensen have initiated the study of wavelets and representations of the Cuntz algebra via branching systems in [3,4]. After this, many results relating branching systems and representations of generalized Cuntz algebras were obtained, see

Ten new triterpenoids, named meliasenins I-R (1-10), one new steroid (11), and 11 related known compounds (12-22) were isolated from fruits of Melia toosendan. The structures of the new compounds were established on the basis of spectroscopic methods, including 2D NMR techniques and mass spectrometry. The relative configuration of 1, (20R*,23E)-25-hydroperoxyeupha-7,23-diene-3β,16β-diol (meliasenin I), was confirmed by single-crystal X-ray diffraction analysis. All isolated triterpenoids (1-10, 12-15) and two steroids (11, 20) were tested for their cytotoxicity against U20S human osteosarcoma and MCF-7 human breast cancer cells using the MTT assay, and some of them were significantly cytotoxic (IC(50) <10 μg/mL). The insecticidal properties of compounds 1-15 and 20 were also briefly evaluated.